PDE4D/cAMP/IL-23 axis determines the immunotherapy efficacy of lung adenocarcinoma via activating the IL-9 autocrine loop of cytotoxic T lymphocytes

Although immunotherapy has changed the prognosis of many advanced malignancies including lung adeno-carcinoma (LUAD), many patients are insensitive to the drugs, with the mechanisms yet to be elucidated. Herein, we identified PDE4D as an immunotherapy efficacy-related gene through bioinformatics screening. By using a co -culture system of LUAD cells and tumor-cell-specific CD8+ T cells, a functional PDE4D/cAMP/IL-23 axis was further revealed in LUAD cells. Fluorescent multiplex immunohistochemistry analysis of patient-derived samples and the in vivo mouse LUAD xenograft tumors revealed not only the colocalization of IL-23 and CD8+ T cells but also the immune potentiating effect of IL-23 on cytotoxic T lymphocytes (CTLs) in LUAD tissues. Through transcriptome sequencing and functional validations, IL-23 was proven to up-regulate IL-9 expression in CTLs via activating the NF-kappa B signaling, leading to elevated productions of immune effector molecules and enhanced efficacy of antitumor immunotherapy. Interestingly, an autocrine loop of IL-9 was also uncovered during this process. In conclusion, PDE4D/cAMP/IL-23 axis determines the immunotherapy efficacy of human LUAD. This effect is mediated by the activation of an NF-kappa B-dependent IL-9 autocrine loop in CTLs.

Automated summary

Through bioinformatics screening, we identified PDE4D as a gene related to immunotherapy efficacy. We discovered a functional PDE4D/cAMP/IL-23 axis in a co-culture system of lung adenocarcinoma cells and tumor-specific CD8+ T cells. Our findings from fluorescent multiplex immunohistochemistry analysis and transcriptome sequencing revealed that IL-23 up-regulates IL-9 expression in CTLs via activating the NF-kappa B signaling pathway, leading to enhanced antitumor immunotherapy efficacy. Additionally, we uncovered an autocrine loop of IL-9 during this process.